Stress urinary incontinence (SUI) is defined as involuntary loss of urine secondary to an increase in abdominal pressure during events such as sneezing, coughing or laughing in the absence of bladder contractions. This disorder is a significant gynecological/urological problem currently affecting approximately 25 million American women. These SUI patients exhibit the high incidence of intrinsic sphincter deficiency, characterized by a malfunction of the urethral sphincter mechanism resulting in the low-pressure urethra. However, normal physiology and pathophysiology of the urethral continence mechanism in relation to SUI are not well elucidated. Thus, utilizing both in-vivo and ex-vivo techniques developed in our laboratory, we propose to perform systematic analyses of urethral continence mechanisms under stress conditions. First, in-vivo neurophysiological analyses will be performed in normal animals and animal models of SUI. Next, ex-vivo biomechanical analyses will be performed of the normal and SUI urethra. Finally, based on these results, we will also seek to explore potential pharmacotherapies of SUI. In this proposal, we hypothesize: 1) the detailed neurophysiological and biomechanical properties contributing to normal urethral continence mechanisms at different positions along the urethra can be identified in normal rats, 2) pathological changes in neurophysiological and biomechanical properties of urethral continence mechanisms can be identified in two different animals models of SUI, and 3) pharmacological treatments using serotonine/norepinephrine reuptake inhibitors and/or adrenoceptor agonists can improve urethral continence mechanisms in two animal models of SUL The Specific Aims of this grant are: I) to characterize the normal physiological and biomechanical properties of the urethral closure mechanisms in normal animals using: a) microtip transducer catheters to measure bladder and urethral responses in-vivo during sneezing or passive increases in intravesical pressure, b) in-vivo leak point pressure measurements during sneezing or passive increases in intravesical pressure, and c) ex-vivo whole urethra biomechanical studies; II) to investigate the pathological changes in the above measurements in two rat models of SUI (vaginal over distension or transection of the nerves to external urethral sphincter and pelvic floor muscles); and III) to investigate possible pharmacotherapies for improving the urethral closure mechanism in the two rat models of SUI. By defining the detailed urethral pathology of SUI, we can offer the hope of prevention and reversal of this potentially devastating condition. This is recognized as a high priority in the urologic/gynecologic care of SUI patients. [unreadable] [unreadable]